Erosive balanitis caused by Staphylococcus haemolyticus in a healthy, circumcised adult male

Introduction. Balanitis is an inflammation of the glans penis. Balanoposthitis involves both the glans penis and prepuce and occurs only in uncircumcised males. Recurrent balanoposthitis represents a strong indication for circumcision. After Candida infections, aerobic bacteria are the second most common aetiological cause of acute infectious balanoposthitis, mainly streptococci groups B and D, and staphylococci, usually S. aureus . Their clinical manifestations are variable inflammatory changes, including diffuse erythema and oedema. Severe balanopreputial oedema with purulent exudate occurs in painful, erosive streptococcal balanoposthitis. Coagulase-negative staphylococci (CoNS) are commensal skin bacteria, but are also recognized pathogens of the genitourinary system, mainly related to urinary tract infections. Staphylococcus haemolyticus is one of the main species of CoNS that is part of the cutaneous microflora but is also associated with nosocomial infections. In addition, S. haemolyticus also causes other infections of the male urogenital tract, such as chronic prostatitis and epididymo-orchitis, but it has not been associated with balanitis. Case presentation. A 45-year-old man reports having suffered several episodes of balanoposthitis in the last 3 years, which were treated with topical antifungal treatments alone or associated with corticosteroids. For this reason, he underwent a postectomy by his urologist 8 months ago to avoid further recurrences. The patient consulted for an episode of painful, erosive and exudative lesions on the glans penis and over the post-operative scars lasting 5 days. He had no urinary discomfort or inguinal lymphadenopathy. A complete blood count, biochemical analysis, C-reactive protein (CRP), prostate-specific antigen (PSA) and urinalysis were normal. Abundant growth of S. haemolyticus was obtained in the culture on tryptone soya agar with sheep blood and chocolate agar with Vitox media. The MicroScan panel CIM 37 (PM37) was used to study the antimicrobial susceptibilities of the isolated bacteria. The fungal culture on Sabouraud dextrose agar was negative. Based on the antimicrobial susceptibility study, treatment with oral ciprofloxacin and topical mupirocin was started, and the genital infection was completely cured. Conclusion. We present a healthy, non-diabetic, circumcised male patient with severe, erosive and painful balanitis probably due to S. haemolyticus .


INTRODUCTION
Balanitis describes inflammation of the glans penis, while balanoposthitis is an inflammation that affects both the glans penis and the foreskin [1].They are much more common in uncircumcised males than in circumcised males, due to the occlusive effect of the prepuce, which facilitates smegma retention and inadequate hygiene [2].
Infectious balanoposthitis is the most frequent of the acute conditions.Candida infections are the most common cause of infectious balanoposthitis and aerobic bacteria are the second most common cause [3].Other non-infectious causes can be traumatic, irritative or contact-based.Chronic balanitis is related to inflammatory or neoplastic dermatoses that affect the genital area.
Coagulase-negative staphylococci (CoNS) are part of the normal microbiota of the skin, but are also known pathogens of the genitourinary system, often implicated in urinary tract infections (UTIs) [4].With respect to the pathogenicity of CoNS, there may be significant differences between species.Thus, Staphylococcus epidermidis and Staphylococcus haemolyticus have a medium pathogenic potential, while S. carnosus is completely apathogenic [5].
S. haemolyticus is one of the main species of CoNS that is part of the cutaneous microflora but is also a frequent nosocomial pathogen, mainly in immunocompromised patients or in catheter-related infections [6].In addition, S. haemolyticus also causes other infections of the male urogenital tract, such as epididymo-orchitis [7] or chronic prostatitis [8], and it could be responsible for male infertility.Infection with this bacterial species decreases sperm motility and viability [6].However, we present this clinical case because we have not found a previous association of S. haemolyticus with balanitis.

CASE REPORT
A 45-year-old man reports having suffered several episodes of balanoposthitis in the last 3 years, which were treated with clotrimazole 1 % cream or miconazole 2 % and hydrocortisone 1 % cream, with only partial responses.The patient was seen in the urologist's office, without performing blood, urine, or microbiological culture tests.Due to the persistence of these episodes, his urologist performed a postectomy 8 months ago to prevent further recurrences.
However, the patient consulted for a new event of painful, erosive, and exudative lesions on the proximal half of the glans penis and over the post-operative scars of 5 days duration (Fig. 1).He had no urinary discomfort or inguinal lymphadenopathy.His wife reported no genital symptoms.A complete blood count, biochemical analysis (glucose, total cholesterol, triglycerides, urea, creatinine, total bilirubin, hepatic transaminases, sodium, potassium), C reactive protein (CRP), prostate specific antigen (PSA) and urinalysis (pH, density, glucose, protein, bilirubin, urobilinogen, ketone bodies, nitrites, red blood cells, leukocytes, microscopic examination of urinary sediment) were requested, and a sample for bacterial culture and another for mycological culture were taken from the glans lesions.
All the blood tests and urinalysis were normal.At 72 h, an abundant growth of S. haemolyticus was obtained in the culture on tryptone soya agar with sheep blood and chocolate agar with Vitox media incubated in 5 % CO 2 at 25 °C.MicroScan -Positive Panel CIM 37 (PM37) was used to study the antimicrobial susceptibilities of the isolated bacteria.The results are shown in Table 1.According to the antibiogram, treatment with ciprofloxacin 500 mg every 12 h orally and with mupirocin 2 % ointment every 8 h was administered for 14 days, and the genital infection was completely cured.The fungal culture on Sabouraud dextrose agar was negative after 21 days.

DISCUSSION
Balanitis is much more common in uncircumcised males than in circumcised males and is also more common in diabetic patients regardless of circumcision status [1].Circumcision is therefore considered to be a surgical intervention to prevent infectious dermatoses of the penis, with or without accompanying phimosis [2].In patients with recurrent balanoposthitis, blood glucose should be investigated for diabetes screening [1].
Yeast infections are the main causes of acute balanoposthitis, especially Candida albicans.The most common causes of bacterial balanoposthitis are streptococci groups B and D, and staphylococci, mainly Staphylococcus aureus [3].In many studies, all patients were uncircumcised [1,2].
The clinical significance of CoNS can be difficult to establish, as they can be either innocuous commensals or invasive pathogens.The immune status of the host will also influence the onset of CoNS disease so that the differences between pathogenic and non-pathogenic CoNS may be blurred [5].However, our patient is a young and healthy male.
Staphylococcus haemolyticus is one of the cutaneous commensal CoNS.It has been observed that this staphylococcal species not only colonizes the skin, but also the urethral and periurethral surfaces of both males and females, causing urinary tract infections (UTIs) in anatomically normal men and women [6].It has also been related to epididymo-orchitis [7] and chronic bacterial prostatitis [8].In these reports, the single isolation of S. haemolyticus in microbiological culture has led to consider it as the aetiological agent.
S. haemolyticus is increasingly implicated in opportunistic infections, including diabetic foot ulcer infections [4].Severe infections such as otitis, endocarditis, prosthetic joint infections, meningitis, peritonitis and bacteraemia have been reported, especially in immunocompromised patients.The presence of venous catheters or medical devices increases the risk of infections due to the ability of S. haemolyticus to form biofilms [6].
S. haemolyticus, especially strains that cause nosocomial infections, are more resistant to antimicrobial drugs than other CoNS and could be an emerging threat today.It seems that the most important factor could be the ability to acquire multidrug resistance to various antibiotics, including glycopeptides [9].However, in our case there was a good response to the antimicrobial treatment administered.
Although S. haemolyticus is one of the most frequently encountered aetiological agents for staphylococcal infections [4], we have not found a previously recorded relationship with balanitis.There is also no mention of its involvement in the European guidelines for the management of balanoposthitis.These indicate that streptococci and S. aureus are the aerobic bacteria that cause balanitis, although others may be involved, but the species are not specified.This paper reports that the clinical manifestations are variable inflammatory changes, including diffuse erythema and oedema, and that treatment is usually topical, while severe cases may require systemic antibiotics, depending on the susceptibilities of the isolated micro-organism [3].In erosive and painful streptococcal balanoposthitis, there may be severe balanopreputial oedema with purulent exudate [10].However, our patient's circumcision should hinder the development of balanitis.
In the study by Deepa et al., S. aureus and Staphylococcus epidermidis were the most frequently isolated bacteria in patients with balanoposthitis [11].Another CoNS, Staphylococcus warneri, has also been associated with balanoposthitis and correlated positively with disease severity [12].In both studies, all patients were uncircumcised.
A case of epididymo-orchitis associated with S. haemolyticus bacteraemia in a healthy adult male has been described [7].This urogenital condition could be due to bacteria found in the urogenital or gastrointestinal tract of a healthy female partner, through vaginal or anal intercourse, causing infection of the urinary bladder or urethra, refluxing to the epididymis and then to the testis.In our case, these bacteria may have only infected the patient's external genitalia.
We believe that S. haemolyticus is the causative agent of the patient's infection; however, the diagnostic evidence is not definitive and may present some limitations, since the infection was caused by a commensal skin staphylococcus isolated from a skin smear taken from a non-sterile area.In addition, the treatment administered was broad spectrum and could cover various Gram-positive and Gram-negative bacteria.
In conclusion, we present a case with severe, erosive and painful balanitis, probably due to S. haemolyticus in a healthy, nondiabetic, circumcised male.To our knowledge, this could be the first reported case of balanitis due to S. haemolyticus.Comments: The authors have taken the reviewer and editorial comments into consideration and the case report is now suitable for acceptance.

Author response to reviewers to Version 2
UPDATEDRESPONSE TO EDITOR AND REVIEWER 1.
-The Editor considered that Figure 2 does not contribute to the understanding of the clinical case and should be removed from the manuscript.Following this recommendation, Figure 2 has been removed from the manuscript.
-The Editor commented that there was no definitive evidence that S. haemolyticuswas the causative agent of the infection.Reviewer 1 commented on the diagnostic uncertainty as S. haemolyticusis a cutaneous commensal that was isolated from a non-sterile area and that the treatment used was broad spectrum which may be valid for a wide variety of gram-positive and gram-negative bacteria.
-So, we have assembled the comments of the Editor and Reviewer 1 in line numbers 152-156 of the manuscript (paragraph 10 of the discussion).In this paragraph we indicate that the diagnostic evidence is not definitive by referring to all the comments of Reviewer 1.
-To avoid making a sweeping diagnostic assertion in this case, we have introduced the term "probably" in line number 44 (conclusion of the abstract) and line number 157 (paragraph 11 of the discussion) of the manuscript.
-We have introduced the sentence "The patient in this case report consented to the publication of this case report" under a 'Consent to Publish' heading (line numbers 201-202).

VERSION 2
Editor Comments: I note responses to the majority of the questions and thank the authors for clarification of how the organism was identified and the drug sensitivities generated and more background information about the case.I still feel that the premise on which the case is built is lacking.In this case the evidence that the infection was caused by the skin commensal staphylococcus haemolyticus is only the result of one skin swab taken at one time point from a non sterile site.The treatment used was also very broad spectrum coving a variety of gram positive and gram negative bacteria.In comparison, the case of epididymo-orchitis associated with S. haemolyticus referenced in the authors conclusions was diagnosed via multiple positive blood culture results.I still believe that the case would benefit from a more clear explanation of the limitations of the diagnostic uncertainty in this case

Please rate the quality of the presentation and structure of the manuscript Satisfactory
To what extent are the conclusions supported by the data?Partially support

Author response to reviewers to Version 1
Erosive balanitis caused by Staphylococcus haemolyticusin a healthy, circumcised adult male.
Response to Reviewers(posted publicly with preprint).

Reviewer 1:
-The patient's visits during the last 3 years were to his urologist, who did not perform any blood tests or microbiological cultures.
-No treatment for staphylococci/streptococci was performed.He was treated topically with antifungal drugs alone or in association with corticosteroids.
-The patient had no systemic disease related to immunosuppression.
-A sample was taken for bacterial culture and another for mycological culture from the glans lesions.
-The culture media used were Tryptone Soya Agar with Sheep Blood and Chocolate Agar with Vitox media incubated in 5% CO2 at 25ºC.
-The MicroScan® -Positive Panel CIM 37 (PM37) was used to study the antimicrobial susceptibilities of the isolated bacteria.
-MALDI-TOF was not used.
-As in our case, there are several reports where the single isolation of S. haemolyticushas been considered as the etiologic agent of these entities.

Reviewer 2:
-S. haemolyticuscauses infections of the male urogenital tract, such as urinary tract infections, chronic prostatitis and epididymoorchitis, but we have not found its relationship with balanitis in the literature review.
-Neither is this staphylococcal species mentioned as a causal agent in the recent 2022 European guideline for the management of balanoposthitis.

-
Erosive balanoposthitis is characteristic of streptococcal infections.Our case has the peculiarity of being produced by a staphylococcal species that has not been related to balanitis and in a circumcised male, which hinders the development of balanoposthitis.
-We have tried to keep the conclusion concise so that it is easy for the reader to understand.This is a case of erosive balanitis, typical of streptococcal infections, in a non-diabetic and circumcised male, which are factors that hinder its occurrence, caused by a staphylococcal species not previously related to balanitis.

Reviewer 3:
-We have slightly modified the title of the manuscript.
-We have increased the size of the abstract and the introduction.
-We have also expanded and updated the number of bibliographical references.
-We have tried to better describe the methodology and results.
-We have tried to correct possible grammatical mistakes in the manuscript.
Comments: 1. Description of the case(s) There are several notes regarding your manuscript as follows.This paper does not fit with the journal topics.The title: I suggest you make a few changes that would be more appropriate to the study.
Abstract -The abstract very short and wasn't included modern tools in this article .-There are several grammatical mistakes that should be corrected.Introduction -Need to add more details about all study subjects about the This subject Infectious balanoposthitis are the most frequent of the acute conditions; other noninfectious causes can be traumatic, irritative or contact.Candida infections are the most common of the infectious balanoposthitis.Bacteria are the second cause in frequency of these acute entities Methodology -Non methodology -Need to add methodology with more details 2. Presentation of results the results non clear ( non-results ) 3. How the style and organization of the paper communicates and represents key findings Research needs attention and writing with modern tools 4. Literature analysis or discussion Research needs attention and writing with modern tools 5.

Please rate the quality of the presentation and structure of the manuscript Very poor
To what extent are the conclusions supported by the data?Not at all

Is there a potential financial or other conflict of interest between yourself and the author(s)? No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?Yes Reviewer 2 recommendation and comments https://doi.org/10.1099/acmi.0.000582.v1.5 © 2023 Anonymous.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License.

Comments:
The work done here is well presented, however there are some comments need to be addressed before accepting for publication.The introduction needs to be rewritten to clarify the research question and research hypothesis.The author need to add in the discussion more explanation and details why although S. haemolyticus is one of the most frequent etiological agents of staphylococcal infections, they have not found its relationship with balanitis.Rewrite the conclusion to add the significant of your case

Please rate the quality of the presentation and structure of the manuscript Satisfactory
To what extent are the conclusions supported by the data?Strongly support

Is there a potential financial or other conflict of interest between yourself and the author(s)? No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?Yes Reviewer 1 recommendation and comments https://doi.org/10.1099/acmi.0.000582.v1.3 © 2023 Anonymous.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License.

Date report received: 22 February 2023 Recommendation: Major Revision
Comments: The authors present a case of erosive balanitis in which they isolate and treat a staphylococcus haemolyticus.While the case is well written and the discussion informative, unfortunately in its current state I do not recommend accepting this paper without major revision.The principal shortcoming of this case lies in the conclusion that the balanitis was caused by the S. haemolyticus.As the authors mention, coagulase negative staphylococcus are common skin commensals and are typically less virulent than the coagulase positive S. Aureus or the streptococcal species which are more commonly associated with skin and soft tissue infections.The article would benefit from more details in support of the assumption that the S. haemolyticus was indeed the causative agent of the balanitis.i.e. was S. haemolyticus cultured on previous occasions when the patient presented over the last 3 years?Did the patient fail any treatment that may have been target toward a sensitive staph / strep i.e flucloxacillin prior to presentation on this occasion?Is there anything else in his history that would you make you suspect that this culture result is significant i.e immunosuppressed in any other way.It is stated that 'samples' were taken, this implies multiple samples were taken from the infected area.If this is the case, how many grew the S. haemolyticus?If multiple were positive this may again be more significant.Related to the above, this case would benefit from more detail, not just in supporting the diagnosis but in better describing the patient's presentation and the microbiological work up.For example.
1. How long had the lesion had been there for?
2. It is stated that the blood tests and urinalysis were normal, it would be useful to know which pertinent tests had been requested even if just a few select but important tests.i.e. his full flood count, CRP etc. 3. Likewise what was tested in the urine? is this how we know he was not diabetic?
3. How was the S. haemolyticus identified i.e was MALDI-TOF used or were more traditional tests used?if MALDI-TOF was used what was the confidence score etc.What specific media was used to culture the bacteria and in what conditions? 4. The authors provide sensitivities in table 1, this is useful for the reader, but it would be good to include how these were arrived at, was disc diffusion testing used? and if any further susceptibility testing was done then including the MICs would add value.In conclusion while the case requires significantly more detail, and the discussion while well written and informative would be improved if more focus was placed on the difficulty of deciding when S. haemolyticus is significant from a skin swab and not just a commensal

Please rate the quality of the presentation and structure of the manuscript Good
To what extent are the conclusions supported by the data?Partially support

Is there a potential financial or other conflict of interest between yourself and the author(s)? No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?Yes

recommendation and comments
This is an open access peer review report distributed under the terms of the Creative Commons Attribution License.
Comments: Thank you for addressing the points raised by the reviewers.However, this report neglects to outline a major limitation of the case.The report presents evidence for S. haemolyticus as the causative agent of infection, however this evidence is not definitive.Please address this limitation, as outlined by reviewer 1, in the report.